14-36684801-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_030631.4(SLC25A21):​c.728G>A​(p.Gly243Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G243R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC25A21
NM_030631.4 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41
Variant links:
Genes affected
SLC25A21 (HGNC:14411): (solute carrier family 25 member 21) SLC25A21 is a homolog of the S. cerevisiae ODC proteins, mitochondrial carriers that transport C5-C7 oxodicarboxylates across inner mitochondrial membranes. One of the species transported by ODC is 2-oxoadipate, a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine in mammals. Within mitochondria, 2-oxoadipate is converted into acetyl-CoA.[supplied by OMIM, Apr 2004]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC25A21NM_030631.4 linkc.728G>A p.Gly243Glu missense_variant Exon 8 of 10 ENST00000331299.6 NP_085134.1 Q9BQT8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC25A21ENST00000331299.6 linkc.728G>A p.Gly243Glu missense_variant Exon 8 of 10 1 NM_030631.4 ENSP00000329452.5 Q9BQT8-1
SLC25A21ENST00000555449.5 linkc.728G>A p.Gly243Glu missense_variant Exon 8 of 11 2 ENSP00000451873.1 Q9BQT8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461792
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Aug 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 243 of the SLC25A21 protein (p.Gly243Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC25A21-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC25A21 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
.;D
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.6
D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.99
.;D
Vest4
0.73
MutPred
0.58
Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);
MVP
0.92
MPC
0.63
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.84
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-37154006; API